Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IκBα kinase and Akt activation

Curcumin (diferuloylmethane), an anti-inflammatory agent used in traditional medicine, has been shown to suppress cellular transformation, proliferation, invasion, angiogenesis, and metastasis through a mechanism not fully understood. Because several genes that mediate these processes are regulated by nuclear factor-kappa B (NF-kappa B), we have postulated that curcumin mediates its activity by modulating NF-kappa B activation. Indeed, our laboratory has shown previously that curcumin can suppress NF-kappa B activation induced by a variety of agents (J Biol Chem 270: 24995 - 50000, 1995). In the present study, we investigated the mechanism by which curcumin manifests its effect on NF-kappa B and NF-kappa B-regulated gene expression. Screening of 20 different analogs of curcumin showed that curcumin was the most potent analog in suppressing the tumor necrosis factor (TNF)-induced NF-kappa B activation. Curcumin inhibited TNF-induced NF-kappa B-dependent reporter gene expression in a dose-dependent manner. Curcumin also suppressed NF-kappa B reporter activity induced by tumor necrosis factor receptor (TNFR) 1, TNFR2, NF-kappa B-inducing kinase, I kappa B kinase complex (IKK), and the p65 subunit of NF-kappa B. Such TNF-induced NF-kappa B-regulated gene products involved in cellular proliferation [cyclooxygenase-2 (COX-2), cyclin D1, and c-myc], antiapoptosis [inhibitor of apoptosis protein (IAP)1, IAP2, X-chromosome-linked IAP, Bcl-2, Bcl-x(L), Bfl-1/A1, TNF receptor-associated factor 1, and cellular Fas-associated death domain protein-like interleukin-1 beta-converting enzyme inhibitory protein-like inhibitory protein], and metastasis (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1) were also down-regulated by curcumin. COX-2 promoter activity induced by TNF was abrogated by curcumin. We found that curcumin suppressed TNF-induced nuclear translocation of p65, which corresponded with the sequential suppression of I kappa B alpha kinase activity, I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 phosphorylation, p65 nuclear translocation, and p65 acetylation. Curcumin also inhibited TNF-induced Akt activation and its association with IKK. Glutathione and dithiothreitol reversed the effect of curcumin on TNF-induced NF-kappa B activation. Overall, our results indicated that curcumin inhibits NF-kappa B activation and NF-kappa B-regulated gene expression through inhibition of IKK and Akt activation.